In this study we will complete our comprehensive characterization of the age-related pathology of all groups of animals in the Biomarker Program, including all 7 genotypes, 2 species, 2 genders and 2 diet groups sacrificed at 6 month intervals. The data will be of great value to other experimental gerontologists. We will also test the hypothetical mechanism that caloric restriction (CR) prolongs life primarily by suppressing cell replication. By doing so it inhibits the development of tumors, the main cause of death of rodents, as well as inflammatory and autoimmune diseases. We will test the hypothesis by collecting and analyzing pathology data to determine the extent to which CR has a greater effect on suppressing proliferative lesions, those involving increases in numbers of cells, than on suppressing degenerative lesions, those involving cell death. We will quantitate the severity of 3 purely degenerative lesions of mice-neuronal lipofuscinosis, neuroaxonal dystrophy and osteopenia, and of 4 lesions that involve cellular replication in response to degenerative processes, arthropathy, white matter gliosis and fibrous osteodystrophy. Further tests of the hypothesis will involve studies of the effects of CR on non-pathologic spontaneous and induced cell replication in hair follicles. We will study the effects of aging and CR on regrowth of hair after shaving and after plucking, which induces follicles into the replicative anagen phase of growth. We will monitor cell replication by labelling hair bulb cells with bromodeoxyuridine. These studies of hair may provide new relatively non-invasive biomarkers of aging.